PROJECT SUMMARY/ABSTRACT: PROJECT 1 Title: Cell context in synovial sarcomagenesis - pathways to therapeutics Synovial sarcoma (SS) is a type of cancer that primarily affects adolescents and young adults, and while the frequency is relatively low, the impact is enormous. Patients are treated with a combination of radiation therapy, chemotherapy, and surgery; however, despite treatment, SS is frequently fatal. SS is caused by a type of genetic alteration called a chromosomal translocation; the specific translocation associated with SS, denoted t(X;18)(p11.2;q11.2), is unique to this cancer. Using this translocation, genetically engineered mouse models have been generated to study SS and have led to significant advancements in our understanding of this cancer; yet much remains unknown. The precise cell type, or cell of origin, that gives rise to SS has not been identified, and the exact mechanisms through which the chromosomal translocation drives the formation of this tumour are not fully understood. Our lab has generated a unique mouse model of SS using mesenchymal stem/progenitor cells, a type of adult stem/progenitor cell that is found throughout the body and plays a variety of critical roles. This model effectively recapitulates synovial sarcoma tumours found in humans and suggests that this population of mesenchymal stem/progenitors cells is a likely candidate for the cell of origin of this cancer. The overarching theme of this grant is to characterize the changes that occur in these cells to transform them from their normal state into a cancerous state, and ultimately to identify new therapeutic targets to treat SS. Taken together, these studies are expected to provide a more thorough understanding of the genesis of SS, and lead to improved treatment strategies and clinical outcomes.